It is generally accepted that lameness due to traumatic joint disease in its various forms is a common clinical problem in horses, and one of the most important sources of financial loses in the equine industry (1-9).
Traumatic arthritis can develop after single or repetitive episodes of trauma, but continued repeated trauma to the joint is held as the most important etiologic factor in traumatic arthritis. The mechanical trauma in the form of stretching, impingement and concussion of articular tissues may perturb cellular membranes, resulting in release of inflammatory mediators inciting joint inflammation. In many cases, extended periods of rest are required for the complete resolution of the joint inflammation. Simple resting of the affected horses is therefore seldom an acceptable therapeutic alternative in working horses, considering the limitations of economics, season and competition schedules (6, 10).
On the other hand, if left without proper treatment and the inciting physical activity is continued, the condition of primary acute synovitis-capsulitis often results in devastating chronic changes of the synovial membrane and fibrous joint capsule associated with articular cartilage degeneration. These changes are known to result from prolonged production of the inflammatory mediators and the subsequent production of enzymes capable of degrading the articular cartilage matrix (4, 8, 9).
For these reasons, safe and effective anti-arthritic medications, to be used concurrently with appropriate rehabilitation exercise programs, are necessary in equine medicine.
Classic treatment options for the aseptic arthritis have consisted of systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs) (8, 10, 11) and intra-articular administration of corticosteroids. Various systemic NSAIDs have been proven effective in reducing discomfort and other clinical signs of inflammation associated with traumatic arthritis (12).
However, it is well known that they are of limited value in modifying the course of the disease when the administration is ceased and therefore recurrence of the clinical signs is common after resuming the intended physical activity. Further, NSAID toxicity, especially in high dose or long term use, is of concern in equine species (12).
Intra-articular injection of corticosteroids was first reported in the horse in 1955 (13). Since then it has become certainly the most widely used intra-articular therapy for equine joint inflammation. According to one report 77% of the equine practitioners responding to a questionnaire administered corticosteroids intra-articularly on a regular basis (11). The recognised extensive use of intra-articular corticosteroids, not only in equine medicine, but in human medicine, has stimulated intense research in this field.
Corticosteroids are very important anti-inflammatory agents, suppressing the formation of several mediators of inflammation and articular cartilage degradative enzymes and, as such, effectively reducing the inflammation and pain associated with traumatic joint disease in horses (10). Although there seems to be good rationale for intra-articular corticosteroid therapy in the horse, the safety of this practice, with respect to the articular cartilage metabolism, has been questioned. Recent experimental research has clearly indicated that intra-articularly administered corticosteroids exert several detrimental effects on articular cartilage in equine species (7, 14-23).
Other agents widely used for the local treatment of aseptic arthritis in horses are sodium hyaluronate and polysulphated glycosaminoglycans (PSGAGs). Both of these agents have been found effective (24) and fulfill many of the criteria for an ideal intra-articular drug, but some problems have also been encountered when using these agents. Limited anti-inflammatory action and high cost are the main drawbacks of the hyaluronate preparations (25) whereas PSGAG has been shown to potentiate the development of iatrogenic septic arthritis (26). Severe aseptic adverse reactions to PSGAG have been reported (27, 28). Multiple injections which are in many cases needed to achieve desired therapeutic results with PSGAG not only increase the risks, but also increase the cost and inconvenience of the treatment.
For the given reasons, it is obviously of interest to search for better alternatives for the local therapy of traumatic arthritis in horses.
Other various active compounds such as phenylacetydroxamic acid, phenoxyacetydroxamic acid, arylacetydroxamic acid and/or their corresponding amides, especially the p-butoxyphenylacetydroxamic acid (called Bufexamac, a non-steroidal anti-inflammatory drug, available as a suspension for intra-articular injection) have been used with success for several years, especially in human rheumatology and sports medicine and the clinical efficacy and good tolerance of these drugs has been, reported (29-36). Some early experimental work also suggests that Bufexamac would have an anabolic effect of articular cartilage metabolism by stimulating the synthesis of glycosaminoglycans. This effect has been shown both in in vivo and in vitro experiments using the rate of radiolabelled sulphur incorporation into the cartilage as a measure for the glycosaminoglycan synthesis (37, 38). These active compounds were described in the patents U.S. Pat. No. 3,479,396, BE-611223, BE-661226, BE-648292, LU-84530, and in the European patent application EP-0116182. However, the use of these active compounds has not been previously reported in equine medicine.
The document WO96/38418-A describes anti-inflammatory pharmaceutical agents useful for treating disorders mediated by cyclooxygenase-2 or 5-lipoxygenase like inflammation and allergic conditions such as asthma; said agents are heterocyclo substituted hydroxamic acid derivatives wherein the core structure is sulfonylphenyl. Besides being useful for human treatment, i.e. treatment of arthritis, these compounds are useful for treatment of mammals, including horses.
The document GB-1250519-A describes cyclodecapentaene derivatives which are anti-inflammatory agents, analgesic agents and anti-pyretic agents, which are useful for the treatment of inflammatory conditions and pain associated therewith such as arthritis. They can be administered and used in the same way as phenylbutazone, orally to animals such as horses.